The selective cleavage of phospholipids and DNA is of critical importance in the DNA repair processes and in the mechanism of action of metallo- chemotherapeutic agents. The design of effective metallo-anticancer and antiviral drugs, whose in vivo target is DNA, depends on a clear understanding of the metal-DNA recognition and of metal-catalyzed phosphodiester hydrolysis. In addition, a large part of the energy currency of living systems is stored in phosphodiester bonds and released through metal-catalyzed phosphate hydrolysis. We propose to address key questions on the nature of metal-nucleotide molecular recognition, phosphate-metal binding and to enhance our understanding of the metal- catalyzed phosphate ester hydrolysis mechanisms by using Rh(III) and Ir(III) complexes as model systems. Substitution-inert transition metal complexes (t1/2 more than 30s) of Co, Rh, and Ir are extremely valuable as model systems for the biologically active metals which are too labile for structural and mechanistic studies. Key advantages of Rh(III) and Ir(III) over Co(III) are the following: i) Rh(III) and Ir(III) complexes are extremely substitution- inert and should allow us to isolate and characterize analogs of reaction intermediates which have been proposed for the corresponding Co(III) systems, ii) their ion size is closer to that of biologically relevant ions such as Mg(II) and Mn(II), and iii) NMR studies of Rh(III) complexes can provide important structural and mechanistic information both by direct observation of the 103Rh nucleus and by coupling to other nuclei in the system. We propose to synthesize, isolate and characterize Rh(III) and Ir(III) complexes of the type [MLchiPn] where L=phosphate moiety. We will study mono-, di, and triphosphate ligands and nucleotides (adenosis, guanosine, cytosine and uridine mono-, di- and triphosphates), including cyclic nucleotides. We will elucidate the mode of phosphate-metal coordination and will isolate and characterize key intermediates in the phosphate hydrolysis reaction.